Abstract:Genome-wide association studies (GWAS) and proteomic studies have provided convincing evidence implicating alterations in immune/inflammatory processes in schizophrenia. However, despite the convergence of evidence, direct links between the genetic and proteomic findings are still lacking for schizophrenia. We investigated associations between single nucleotide polymorphisms (SNPs) from the custom-made PsychArray and the expression levels of 190 multiplex immunoassay profiled serum proteins in 149 schizophreni… Show more
“…The anthropometric and social traits also formed a sub-group, except BMI that was distantly located. The immune group and the neurological/neuropsychiatric group were close to each other, which was expected because many previous works have reported that immune related processes are widely involved in several neurological/neuropsychiatric traits such as SCZ [33] and ALZ [34]. Fig.…”
BackgroundGenome-wide association studies (GWAS) have been successful in identifying disease-associated genetic variants. Recently, an increasing number of GWAS summary statistics have been made available to the research community, providing extensive repositories for studies of human complex diseases. In particular, cross-trait associations at the genetic level can be beneficial from large-scale GWAS summary statistics by using genetic variants that are associated with multiple traits. However, direct assessment of cross-trait associations using susceptibility loci has been challenging due to the complex genetic architectures in most diseases, calling for advantageous methods that could integrate functional interpretation and imply biological mechanisms.ResultsWe developed an analytical framework for systematic integration of cross-trait associations. It incorporates two different approaches to detect enriched pathways and requires only summary statistics. We demonstrated the framework using 25 traits belonging to four phenotype groups. Our results revealed an average of 54 significantly associated pathways (ranged between 18 and 175) per trait. We further proved that pathway-based analysis provided increased power to estimate cross-trait associations compared to gene-level analysis. Based on Fisher’s Exact Test (FET), we identified a total of 24 (53) pairs of trait-trait association at adjusted pFET < 1 × 10− 3 (pFET < 0.01) among the 25 traits. Our trait-trait association network revealed not only many relationships among the traits within the same group but also novel relationships among traits from different groups, which warrants further investigation in future.ConclusionsOur study revealed that risk variants for 25 different traits aggregated in particular biological pathways and that these pathways were frequently shared among traits. Our results confirmed known mechanisms and also suggested several novel insights into the etiology of multi-traits.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-5373-7) contains supplementary material, which is available to authorized users.
“…The anthropometric and social traits also formed a sub-group, except BMI that was distantly located. The immune group and the neurological/neuropsychiatric group were close to each other, which was expected because many previous works have reported that immune related processes are widely involved in several neurological/neuropsychiatric traits such as SCZ [33] and ALZ [34]. Fig.…”
BackgroundGenome-wide association studies (GWAS) have been successful in identifying disease-associated genetic variants. Recently, an increasing number of GWAS summary statistics have been made available to the research community, providing extensive repositories for studies of human complex diseases. In particular, cross-trait associations at the genetic level can be beneficial from large-scale GWAS summary statistics by using genetic variants that are associated with multiple traits. However, direct assessment of cross-trait associations using susceptibility loci has been challenging due to the complex genetic architectures in most diseases, calling for advantageous methods that could integrate functional interpretation and imply biological mechanisms.ResultsWe developed an analytical framework for systematic integration of cross-trait associations. It incorporates two different approaches to detect enriched pathways and requires only summary statistics. We demonstrated the framework using 25 traits belonging to four phenotype groups. Our results revealed an average of 54 significantly associated pathways (ranged between 18 and 175) per trait. We further proved that pathway-based analysis provided increased power to estimate cross-trait associations compared to gene-level analysis. Based on Fisher’s Exact Test (FET), we identified a total of 24 (53) pairs of trait-trait association at adjusted pFET < 1 × 10− 3 (pFET < 0.01) among the 25 traits. Our trait-trait association network revealed not only many relationships among the traits within the same group but also novel relationships among traits from different groups, which warrants further investigation in future.ConclusionsOur study revealed that risk variants for 25 different traits aggregated in particular biological pathways and that these pathways were frequently shared among traits. Our results confirmed known mechanisms and also suggested several novel insights into the etiology of multi-traits.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-5373-7) contains supplementary material, which is available to authorized users.
“…Our observation that expression of immunological process related genes vary with cognitive performance in familial schizophrenia further supports the genomic discoveries made (Chan et al, 2017;Gardiner et al, 2013;Schizophrenia Working Group of the Psychiatric Genomics, 2014;Schmitt et al, 2011;Wu et al, 2016;Xu et al, 2012), suggesting that inflammatory responses are related to the pathophysiology and development of schizophrenia. Thus immune or inflammatory processes may be of biological interest for future drug design towards schizophrenia and the cognitive dysfunctions that underlie it.…”
Section: Discussionsupporting
confidence: 84%
“…HLA-G gene) showed enrichment in a study of schizophrenia patients with cognitive impairment (Wu et al, 2016). Thus there is a growing body of evidence suggesting that the aetiology of schizophrenia may involve infectious or autoimmune processes from epidemiological (Feigenson et al, 2014), genome-wide loci (Schizophrenia Working Group of the Psychiatric Genomics, 2014), genetic and proteomic (Chan et al, 2017), and gene expression (Gardiner et al, 2013;Schmitt et al, 2011;Wu et al, 2016;Xu et al, 2012) approaches.…”
Schizophrenia is a heterogeneous disorder characterized by a spectrum of symptoms and many different underlying causes. Thus, instead of using the broad diagnosis, intermediate phenotypes can be used to possibly decrease the underlying complexity of the disorder. Alongside the classical symptoms of delusions and hallucinations, cognitive deficits are a core feature of schizophrenia. To increase our understanding of the biological processes related to these cognitive deficits, we performed a genome-wide gene expression analysis. A battery of 14 neuropsychological tests was administered to 844 individuals from a Finnish familial schizophrenia cohort. We grouped the applied neuropsychological tests into five factors for further analysis. Cognitive endophenotypes, whole blood mRNA, genotype, and medication use data were studied from 47 individuals. Expression level of several RNA probes were significantly associated with cognitive performance. The factor representing Verbal Working Memory was associated with altered expression levels of 11 probes, of which one probe was also associated with a specific sub-measure of this factor (WMS-R Digit span backward). While, the factor Processing speed was related to one probe, which additionally associated among 55 probes with a specific sub-measure of this factor (WAIS-R Digit symbol). Two probes were associated with the measure recognition memory performance. Enrichment analysis of these differentially expressed probes highlighted immunological processes. Our findings are in line with genome-wide genetic discoveries made in schizophrenia, suggesting that immunological processes may be of biological interest for future drug design towards schizophrenia and the cognitive dysfunctions that underlie it.
“…Regarding its brain function, α1AT has been proposed to be involved in Alzheimer’s disease (AD) (68), Parkinson’s disease (PD) (69), schizophrenia (70), and amyotrophic lateral sclerosis (ALS) (71), but no specific mechanisms have been described. α1AT has been shown to drastically reduce excitotoxicity in vitro through the inhibition of calpain (72), but there is no evidence of this phenomenon being physiologically significant in vivo .…”
Rett syndrome is a rare neuropsychiatric disorder with a wide symptomatology including impaired communication and movement, cardio-respiratory abnormalities, and seizures. The clinical presentation is typically associated to mutations in the gene coding for the methyl-CpG-binding protein 2 (
MECP2
), which is a transcription factor. The gene is ubiquitously present in all the cells of the organism with a peak of expression in neurons. For this reason, most of the studies in Rett models have been performed in brain. However, some of the symptoms of Rett are linked to the peripheral expression of
MECP2
, suggesting that the effects of the mutations affect gene expression levels in tissues other than the brain. We used RNA sequencing in
Mecp2
mutant mice and matched controls, to identify common genes and pathways differentially regulated across different tissues. We performed our study in brain and peripheral blood, and we identified differentially expressed genes (DEGs) and pathways in each tissue. Then, we compared the genes and mechanisms identified in each preparation. We found that some genes and molecular pathways that are differentially expressed in brain are also differentially expressed in blood of
Mecp2
mutant mice at a symptomatic—but not presymptomatic—stage. This is the case for the gene
Ube2v1
, linked to ubiquitination system, and
Serpin1
, involved in complement and coagulation cascades. Analysis of biological functions in the brain shows the enrichment of mechanisms correlated to circadian rhythms, while in the blood are enriched the mechanisms of response to stimulus—including immune response. Some mechanisms are enriched in both preparations, such as lipid metabolism and response to stress. These results suggest that analysis of peripheral blood can reveal ubiquitous altered molecular mechanisms of Rett and have applications in diagnosis and treatments’ assessments.
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